Non-clinical safety assessment of single and repeated intramuscular administration of a human papillomavirus-16/18 vaccine in rabbits and rats

The human papillomavirus (HPV)‐16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus‐like particles assembled from the L1 major capsid proteins of the cervical cancer‐causing viral types HPV‐16 and HPV‐18, and Adjuvant Syste...

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Bibliographic Details
Published in:Journal of applied toxicology 2015-12, Vol.35 (12), p.1577-1585
Main Authors: Segal, Lawrence, Morelle, Danielle, Kaaber, Kari, Destexhe, Eric, Garçon, Nathalie
Format: Article
Language:English
Subjects:
Adjuvant System
aluminium hydroxide
Aluminum Hydroxide - administration & dosage
Aluminum Hydroxide - immunology
Aluminum Hydroxide - toxicity
Animals
Cervical cancer
Circulating
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Female
Human
Human papillomavirus
Human papillomavirus 16 - immunology
Human papillomavirus 18 - immunology
human papillomavirus vaccine
Injections, Intramuscular
Lipid A - administration & dosage
Lipid A - analogs & derivatives
Lipid A - immunology
Lipid A - toxicity
monophosphoryl lipid A
Papillomavirus Infections - immunology
Papillomavirus Infections - prevention & control
Papillomavirus Vaccines - administration & dosage
Papillomavirus Vaccines - immunology
Papillomavirus Vaccines - toxicity
Rabbits
Rats
Recombinant
Rodents
Toxicology
Uterine Cervical Neoplasms - immunology
Uterine Cervical Neoplasms - prevention & control
Vaccines
virus-like particle
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Summary:The human papillomavirus (HPV)‐16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus‐like particles assembled from the L1 major capsid proteins of the cervical cancer‐causing viral types HPV‐16 and HPV‐18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV‐16/18 vaccine or AS04 alone, three repeated‐dose studies were performed in rabbits and rats. One rabbit study also included a single‐dose evaluation. In rabbits (~2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (~250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment‐related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment‐related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV‐16/18 vaccine. Additional treatment‐related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle‐fibre regeneration and focal points of macrophage infiltration. Therefore, in these non‐clinical models, the single and repeated dose administrations of the HPV‐16/18 vaccine or AS04 alone were safe and well tolerated. Copyright © 2015 John Wiley & Sons, Ltd. The human papillomavirus vaccine Cervarix® is for the prevention of cervical cancer. It contains recombinant virus‐like particles and AS04 (MPL and aluminium salt). Local and systemic toxic effects of Cervarix® or AS04 were evaluated in repeated‐dose studies in rabbits and rats. Treatment‐related changes included a slight transient increase in circulating neutrophils and injection site inflammation. Thirteen weeks post‐fourth dose, recovery at the injection site was near complete. Therefore in these non‐clinical models, Cervarix® and AS04 alone were safe and well tolerated.
ISSN:0260-437X
1099-1263
DOI:10.1002/jat.3131