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.