Safety and Immunogenicity Study on Recombinant Nine-Valent Human Papillomavirus Vaccine in Rats / 中国药学杂志

ABSTRACT

OBJECTIVE To investigate nonclinical safety and immunogenicity of the recombinant nine-valent human papillomavirus vaccine(9vHPV vaccine) through repeated dose to rats, and provide reference for the dose level design and side effects monitoring in clinical trials. METHODS: Wistar rats were used and divided into four main toxicity groups: negative control, adjuvant control, low dose HPV vaccine group(1/2 dose•rat-1) and high dose HPV vaccine group(2 dose•rat-1). Each group had a satellite group. Animals were dosed by intramuscular injection in weeks 0, 2, 4 and 6 respectively. During the study, all the animals were observed for clinical signs and injection site irritations. For main toxicity groups, body weights, food consumption and body temperature were measured, and ophthalmologic examination, urinalysis, hematology, coagulation, serum chemistry examinations and T lymphocyte subset assay in peripheral blood were done at terminal and recovery necropsy respectively. A full necropsy was then conducted on animals, and tissues were weighed and processed for microscopic examination. Serum anti-HPV binding antibody and neutralizing antibody and antinuclear antibody were determined for satellite animals. RESULTS: Rats produced high levels of anti-HPV binding antibody and neutralizing antibody with strong activity to the nine antigens contained in the low and high dose HPV vaccines. The low and high dose vaccine and the adjuvant caused the increases in peripheral blood neutrophils and eosinophils, which basically recovered three weeks post the last dose. Both the adjuvant and the two dose levels of vaccine led to the slight decrease in serum ALB, increase in globulin and the decrease in A/G ratio in treated rats. Adjuvant and vaccine-related gross necropsy changes were white spots in bilateral injection site muscles. Treatment-related microscopic findings were the degeneration and necrosis of muscle fibers, mixed inflammatory cell infiltration and hyperplasia of fibrous tissue in injection site muscles, and the mixed inflammatory cell infiltration and hyperplasia of fibrous tissue around the sciatic nerve sheath, which partially recovered at the end of the recovery period. The HPV vaccine did not have obvious impact on other end points determined. CONCLUSION: The low and high dose vaccine and the adjuvant can cause the following changes in rats: the increases in peripheral blood neutrophils and eosinophils, the increase in serum globulin and the pathological irritation changes at injection sites. The 9vHPV vaccine has a good safety profile in Wistar rats under the dose levels of this study, with the no observed adverse effect level of 2 dose•rat-1.