INTRODUCTION: Inflammatory reactions are one of the potential safety concerns that are evaluated in the framework of vaccine safety testing. In nonclinical studies, the assessment of the inflammation relies notably on the measurement of biomarkers. C-reactive protein (CRP) is an acute-phase plasma protein of hepatic origin that could be used for that purpose in toxicity studies with rabbits. METHODS: To evaluate the utility of CRP as an additional inflammatory biomarker in adjuvant or vaccine toxicity studies, rabbits were injected on Day 0 with saline, aluminium phosphate, aluminium hydroxide, Adjuvant System (AS)01, AS03, AS15, or diphtheria-tetanus-whole cell pertussis-hepatitis B vaccine (DTPw-HB). Body weights, haematology parameters, CRP and fibrinogen levels were measured daily up to Day 7. Macroscopic changes at the injection site were also evaluated up to Day 7. At Day 7, a histopathological examination of the injection site was performed. RESULTS: Like fibrinogen, CRP levels rapidly increased after the injection of Adjuvant Systems or DTPw-HB, peaking at Day 1, and returning to baseline in less than a week. The magnitude of the CRP increase was consistently higher than that of fibrinogen with a larger fold increase from background, providing a more sensitive evaluation. The number of circulating heterophils was also increased on Day 1 after the injection of Adjuvant Systems or DTPw-HB. The highest increases in CRP levels were observed after the injection of DTPw-HB or AS03, and were also associated with the persistence of mixed inflammatory cell infiltrates (including heterophils) at the injection sites on Day 7. No increases in CRP levels and in circulating heterophils were observed after injection of the aluminium salt adjuvants. DISCUSSION: Our study supports the use of CRP as an accurate biomarker of acute inflammation in rabbits for vaccine toxicity studies and highlights an association between increased CRP levels and the recruitment of heterophils.
INTRODUCTION: Inflammatory reactions are one of the potential safety concerns that are evaluated in the framework of vaccine safety testing. In nonclinical studies, the assessment of the inflammation relies notably on the measurement of biomarkers. C-reactive protein (CRP) is an acute-phase plasma protein of hepatic origin that could be used for that purpose in toxicity studies with rabbits. METHODS: To evaluate the utility of CRP as an additional inflammatory biomarker in adjuvant or vaccine toxicity studies, rabbits were injected on Day 0 with saline, aluminium phosphate, aluminium hydroxide, Adjuvant System (AS)01, AS03, AS15, or diphtheria-tetanus-whole cell pertussis-hepatitis B vaccine (DTPw-HB). Body weights, haematology parameters, CRP and fibrinogen levels were measured daily up to Day 7. Macroscopic changes at the injection site were also evaluated up to Day 7. At Day 7, a histopathological examination of the injection site was performed. RESULTS: Like fibrinogen, CRP levels rapidly increased after the injection of Adjuvant Systems or DTPw-HB, peaking at Day 1, and returning to baseline in less than a week. The magnitude of the CRP increase was consistently higher than that of fibrinogen with a larger fold increase from background, providing a more sensitive evaluation. The number of circulating heterophils was also increased on Day 1 after the injection of Adjuvant Systems or DTPw-HB. The highest increases in CRP levels were observed after the injection of DTPw-HB or AS03, and were also associated with the persistence of mixed inflammatory cell infiltrates (including heterophils) at the injection sites on Day 7. No increases in CRP levels and in circulating heterophils were observed after injection of the aluminium salt adjuvants. DISCUSSION: Our study supports the use of CRP as an accurate biomarker of acute inflammation in rabbits for vaccine toxicity studies and highlights an association between increased CRP levels and the recruitment of heterophils.
Authors: Ugur Sahin; Alexander Muik; Isabel Vogler; Evelyna Derhovanessian; Lena M Kranz; Mathias Vormehr; Jasmin Quandt; Nicole Bidmon; Alexander Ulges; Alina Baum; Kristen E Pascal; Daniel Maurus; Sebastian Brachtendorf; Verena Lörks; Julian Sikorski; Peter Koch; Rolf Hilker; Dirk Becker; Ann-Kathrin Eller; Jan Grützner; Manuel Tonigold; Carsten Boesler; Corinna Rosenbaum; Ludwig Heesen; Marie-Cristine Kühnle; Asaf Poran; Jesse Z Dong; Ulrich Luxemburger; Alexandra Kemmer-Brück; David Langer; Martin Bexon; Stefanie Bolte; Tania Palanche; Armin Schultz; Sybille Baumann; Azita J Mahiny; Gábor Boros; Jonas Reinholz; Gábor T Szabó; Katalin Karikó; Pei-Yong Shi; Camila Fontes-Garfias; John L Perez; Mark Cutler; David Cooper; Christos A Kyratsous; Philip R Dormitzer; Kathrin U Jansen; Özlem Türeci Journal: Nature Date: 2021-05-27 Impact factor: 49.962
Authors: Camille Planty; Corey P Mallett; Kevin Yim; Jorge C G Blanco; Marina Boukhvalova; Thomas March; Robbert van der Most; Eric Destexhe Journal: Hum Vaccin Immunother Date: 2016-09-14 Impact factor: 3.452
Authors: Wivine Burny; Andrea Callegaro; Viviane Bechtold; Frédéric Clement; Sophie Delhaye; Laurence Fissette; Michel Janssens; Geert Leroux-Roels; Arnaud Marchant; Robert A van den Berg; Nathalie Garçon; Robbert van der Most; Arnaud M Didierlaurent Journal: Front Immunol Date: 2017-08-14 Impact factor: 7.561